Persons who are exposed to cytotoxic agents are at risk of developing acute myeloid leukemia (t-AML), myelodysplastic syndrome (t-MDS), and myelodysplastic syndrome/myeloproliferative neoplasms (t-MDS/MPN). These conditions lie along a continuum of disease and are categorized by the World Health Organization (WHO) classification system as therapy-related myeloid neoplasms (t-MN) [1,2]. t-MN is a clinical syndrome that is distinguished by iatrogenic exposure to mutagenic agents. Excluded from this category is progression of myeloproliferative neoplasms (MPNs) and evolution of primary MDS to AML (so-called "secondary" AML); in both of these latter cases, evolution to AML is part of the natural history of the primary disease and it may be impossible to distinguish natural progression from therapy-induced changes [3].

Patients with t-MN comprise a heterogeneous and poorly defined group who have a shorter median survival than patients with de novo AML, MDS, or MDS/MPN. This subset of myeloid neoplasms shares many clinical and biological characteristics of leukemias and MDS/MPN that appear de novo (ie, with no known exposure to mutagenic agents). However, the t-MN cases most often have high-risk or adverse features, and as a group have had poor outcomes independent of other established AML prognostic factors. They are identified and classified as a defined subgroup largely to better understand how known mutagenic exposures impact human hematopoietic stem cells to give rise to malignancy. Undoubtedly, some patients who fall into this category based solely on their medical history have developed a myeloid malignancy independent from prior cytotoxic exposures, but these de novo cases cannot be distinguished currently.

Therapy-related myeloid neoplasms (t-MN) account for approximately 10 to 20 percent of all cases of AML, MDS, and MDS/MPN [4]. The incidence among patients treated with cytotoxic agents varies according to the underlying disease, specific agents, timing of exposure, and dose [5]. Patients can present at any age, but the median age at diagnosis is 61 years [6,7]. The risk associated with alkylating agents and radiation appears to increase with age, while the risk associated with topoisomerase II inhibitors appears to be constant across all ages [1]. Only a small percentage of patients treated with identical cytotoxic regimens develop t-MN; this may suggest that some individuals may have a heritable predisposition due to mutations in DNA damage sensing or repair genes (eg, BRCA1/2 or TP53), or polymorphisms in genes that affect drug metabolism, transport, or DNA-repair mechanisms [8,9].

The proportion of patients with a prior hematologic malignancy or a prior solid tumor is approximately equal and accounts for the large majority of cases. Five to 20 percent of patients will have a history of exposure to cytotoxic therapy for benign disorders while a similar proportion will have undergone an autologous hematopoietic cell transplantation (HCT) [4].

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